The present invention relates to the preparation of 13-(Z)-retinoic acid (I) by reacting 5-hydroxy-4-methyl-2(5H)-furanone (II; butenolide) with a [3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadienyl]triarylpho sphonium salt (C.sub.15 -triarylphosphonium salt) and subsequently partially isomerizing the resulting mixture of 13-(Z)- and 11,13-di-(Z)-retinoic acid (also called 13-cis- and 11,13-di-cis-retinoic acid or -vitamin A acid).
13-(Z)-Retinoic acid is a substance of pharmacological importance for the treatment of acne. Its synthesis is relatively difficult because of the formation of double-bond isomers.
Thus, for example, a synthesis described in J. Chem. Soc. (C) (1968) 1984-97 from butenolide II and a C.sub.15 -triarylphosphonium salt in diethyl ether results in a mixture of 13-(Z)- and 11,13-di-(Z)-retinoic acid in a yield of 66 to 75% of theory, where the content of the 13-(Z)-isomers is only about 36%. Selective isomerization of the 11-(Z) double bonds in the presence of a 13-(Z) double bond proves impossible.
Furthermore, EP-B1-0 111 325 discloses a process for preparing 13-(Z)-retinoic acid by coupling a C.sub.15 -triarylphosphonium salt to the butenolide II and subsequently isomerizing in the presence of transition metal catalysts. This process is intrinsically good but has the disadvantage that the Wittig reaction must be carried out at, preferably, from -30.degree. to -45.degree. C., which entails very high energy costs. In addition, an elaborate extraction procedure is necessary.
The subsequent selective isomerization of 11,13-di-(Z)-retinoic acid takes place in very good yields but the use of the isomerization catalysts described therein leads to contamination of the required product with traces of transition metals, which may lead to problems with the stability of the required product. Contamination of the required product with organic phosphorus from the addition of triphenylphosphine to decomplex the catalyst makes additional purification steps necessary. Furthermore, treatment of the required product with acetonitrile as solvent for the isomerization catalyst is not without problems.